Computer Simulations Helped to Detect Drugs for Heart Disorders

Over time, the phospholipids in this outer layer become oxidized, attracting free radicals and further oxidation, contributing to plaque buildup and cardiovascular disease.

Lp-PLA2 extracts these oxidized phospholipids from the lipoprotein membrane and releases their fatty acids further metabolized. Understanding exactly how these process works creates new opportunities for therapeutics against cardiovascular disease.

“I am very pleased that we were able to go into much greater depth on how this enzyme works than ever before,” said Edward A. Dennis, PhD, senior author of the study and Distinguished Professor of Pharmacology, Chemistry, and Biochemistry at UC San Diego School of Medicine.

“Using the latest advances in lipidomics and computational molecular dynamics simulations, we got a picture which is worth a thousand words.

We now have movies that show how this enzyme works at the atomic level, and that should help us figure out ways to activate or inactivate the enzyme as necessary for health.”

This advanced approach revealed a specific peptide region consisting of two alpha helices connected with a loop that acts as a gate to the enzyme’s active site.

Typically, this gate is in a “closed” position, but when Lp-PLA2 binds to the phospholipid membrane, it undergoes an allosteric conformational change that opens the gate and increases the volume of the active site.

Dennis’ team, led by first author Varnavas D. Mouchlis, PhD, also showed which oxidized phospholipid substrates Lp-PLA2 have the greatest affinity. They further identified a binding pocket distinct from known drug inhibitor binding pockets, which may serve as a new target for future therapeutic drugs.

The research group had previously introduced the concept of membrane-facilitated allosteric regulation of PLA2 enzymes but had until this point only studied enzymes that function on phospholipid bilayers .

This study confirmed that a similar mechanism could be used to facilitate phospholipase action on phospholipid monolayers, such as those on lipoproteins.

“PLA2 enzymes have all sorts of important functions in inflammation, digestion, brain health, and more, so it’s amazing to see this wide variety of enzymes all show a similar action strategy,” said Dennis.

“We’ve been studying this superfamily of enzymes for almost 50 years, so to finally have this complete picture of how they work is really satisfying, and the whole field advances.”

Source: Medindia